rs80008695

chr4-78363685-A-Cchr4-78363685-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025074.7(FRAS1):c.2575+20A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,566,466 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (63 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.479

Genes affected

FRAS1 (HGNC:19185): (Fraser extracellular matrix complex subunit 1) This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-78363685-A-C is Benign according to our data. Variant chr4-78363685-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 445933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00503 (766/152296) while in subpopulation AMR AF= 0.0466 (712/15294). AF 95% confidence interval is 0.0437. There are 22 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.2575+20A>C		intron_variant		ENST00000512123.4
FRAS1	NM_001166133.2	c.2575+20A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.2575+20A>C		intron_variant		5	NM_025074.7	P1
FRAS1	ENST00000325942.11	c.2575+20A>C		intron_variant		1
FRAS1	ENST00000682513.1	c.2575+20A>C		intron_variant
FRAS1	ENST00000684159.1	c.2575+20A>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 767 AN: 152178 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00787 AC: 1390 AN: 176542 Hom.: 46 AF XY: 0.00614 AC XY: 573 AN XY: 93340

Gnomad AFR exome AF: 0.000720

Gnomad AMR exome AF: 0.0519

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00139 AC: 1963 AN: 1414170 Hom.: 63 Cov.: 32 AF XY: 0.00119 AC XY: 832 AN XY: 698798

Gnomad4 AFR exome AF: 0.000372

Gnomad4 AMR exome AF: 0.0495

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000267

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152296 Hom.: 22 Cov.: 32 AF XY: 0.00616 AC XY: 459 AN XY: 74480

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.00720

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.8
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80008695; hg19: chr4-79284839;